The extracellular matrix (ECM) and ECM receptors regulate the tissue response to lung injury. One matrix component that has been shown to be produced in increased amounts following lung injury is the glycosaminoglycan hyaluronan (HA). HA accumulation is maximal during the peak of lung injury and is subsequently cleared. Following lung injury, HA breakdown products are generated. These HA fragments induce the expression of a number of key inflammatory mediators in alveolar macrophages such as chemokines, reactive oxygen and nitrogen species and proteases. Using a non-infectious model of lung injury and repair, we provide evidence that the HA receptor CD44 is required to resolve lung inflammation. CD44-deficient mice exhibit a defect in clearance of HA fragments. In addition, HA fragments induce inflammatory genes in CD44-deficient macrophages. We have generated data that implicate Toll-like receptors in mediating HA signaling. The failure to clear HA fragments following lung injury is associated with persistent lung inflammation and death. This has led us to formulate the following hypotheses: HA fragments generated as a result of non-infectious lung injury are important mediators of lung inflammation, CD44 is required to resolve lung inflammation and a TLR mediates HA signaling in macrophages. We will test these hypotheses in the following Specific Aims: 1) Characterize the mechanisms by which CD44 mediates the resolution of non-infectious lung inflammation. 2) Determine the direct contribution of HA accumulation in vivo to lung inflammation using mice genetically engineered to overexpress HA in a lung-specific manner and mice with targeted deletions of hyaluronan synthase isoforms. 3) Determine the direct contribution of the accumulation of HA fragments in vivo to lung inflammation using mice genetically engineered to overexpress a novel hyaluronidase in an inducible, lung-specific manner. 4) Characterize the role of Toll-like receptor 2 in mediating HA fragment-induced gene expression in vitro using TLR2 and MyD88-deficient mice.